HOTAIR interacts with PRC2 complex regulating the regional preadipocyte transcriptome and human fat distribution
Feng-Chih Kuo,
Matt J. Neville,
Rugivan Sabaratnam,
Agata Wesolowska-Andersen,
Daniel Phillips,
Laura B.L. Wittemans,
Andrea D. van Dam,
Nellie Y. Loh,
Marijana Todorčević,
Nathan Denton,
Katherine A. Kentistou,
Peter K. Joshi,
Constantinos Christodoulides,
Claudia Langenberg,
Philippe Collas,
Fredrik Karpe,
Katherine E. Pinnick
Affiliations
Feng-Chih Kuo
Oxford Centre for Diabetes, Endocrinology, and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Headington OX3 7LE, UK; Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defence Medical Centre, Taipei, Taiwan
Matt J. Neville
Oxford Centre for Diabetes, Endocrinology, and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Headington OX3 7LE, UK; NIHR Oxford Biomedical Research Centre, OUH Foundation Trust, Oxford, UK
Rugivan Sabaratnam
Oxford Centre for Diabetes, Endocrinology, and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Headington OX3 7LE, UK; Institute of Clinical Research, University of Southern Denmark, 5000 Odense C, Denmark; Steno Diabetes Center Odense, Odense University Hospital, 5000 Odense C, Denmark
Agata Wesolowska-Andersen
Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
Daniel Phillips
Oxford Centre for Diabetes, Endocrinology, and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Headington OX3 7LE, UK
Laura B.L. Wittemans
MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, UK; The Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK
Andrea D. van Dam
Oxford Centre for Diabetes, Endocrinology, and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Headington OX3 7LE, UK
Nellie Y. Loh
Oxford Centre for Diabetes, Endocrinology, and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Headington OX3 7LE, UK
Marijana Todorčević
Oxford Centre for Diabetes, Endocrinology, and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Headington OX3 7LE, UK
Nathan Denton
Oxford Centre for Diabetes, Endocrinology, and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Headington OX3 7LE, UK
Katherine A. Kentistou
Centre for Global Health Research, Usher Institute, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK; Centre for Cardiovascular Sciences, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
Peter K. Joshi
Centre for Global Health Research, Usher Institute, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK
Constantinos Christodoulides
Oxford Centre for Diabetes, Endocrinology, and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Headington OX3 7LE, UK
Claudia Langenberg
MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, UK
Philippe Collas
Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Immunology, Oslo University Hospital, Oslo, Norway
Fredrik Karpe
Oxford Centre for Diabetes, Endocrinology, and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Headington OX3 7LE, UK; NIHR Oxford Biomedical Research Centre, OUH Foundation Trust, Oxford, UK; Corresponding author
Katherine E. Pinnick
Oxford Centre for Diabetes, Endocrinology, and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Headington OX3 7LE, UK; Corresponding author
Summary: Mechanisms governing regional human adipose tissue (AT) development remain undefined. Here, we show that the long non-coding RNA HOTAIR (HOX transcript antisense RNA) is exclusively expressed in gluteofemoral AT, where it is essential for adipocyte development. We find that HOTAIR interacts with polycomb repressive complex 2 (PRC2) and we identify core HOTAIR-PRC2 target genes involved in adipocyte lineage determination. Repression of target genes coincides with PRC2 promoter occupancy and H3K27 trimethylation. HOTAIR is also involved in modifying the gluteal adipocyte transcriptome through alternative splicing. Gluteal-specific expression of HOTAIR is maintained by defined regions of open chromatin across the HOTAIR promoter. HOTAIR expression levels can be modified by hormonal (estrogen, glucocorticoids) and genetic variation (rs1443512 is a HOTAIR eQTL associated with reduced gynoid fat mass). These data identify HOTAIR as a dynamic regulator of the gluteal adipocyte transcriptome and epigenome with functional importance for human regional AT development.
